Some aminohydroxy-propoxyimino derivatives are known in the art but their chemical structure and pharmaceutical activity are very different from those of the compounds of the present invention.
The fluorene derivative "IPS-339" of formula (a) ##STR3## exhibits beta-adrenergic blocking effect.
The methyl cyclohexylketone derivative of formula (b) ##STR4## (known as Falintolol) also exhibits beta-adrenergic blocking activity.
Compound of formula (c) (known as Paradoxime) ##STR5## shows blood pressure reducing activity.
Peraclopone (compound of formula d) ##STR6## reduces the level of lipids.
Belgian patent specification No. 886,471 describes compounds of formula IX ##STR7## wherein L represents benzothiophene group, while B stands for a secondary amine group. The compounds exhibit beta-adrenergic blocking and antiarrhythmic activity.
Published PCT patent application No. 8402908 relates to carbostiryl ketoxime derivatives exhibiting not only beta-adrenergic blocking activity but antiglaucomic activity as well.
Belgian patent specification No. 838,440 describes beta-adrenergic blocking, blood pressure reducing and cardiovascular compounds of formula IX, wherein L represents a polycyclic ring (e.g. fluorene, indane, xanthane, tetrahydro naphthalene, etc.) or phenyl or naphthyl ketone and B always stands for a secondary amino group.
U.S. Pat. No. 4,652,586 relates to compounds of formula IX, wherein L is fluorene and B is a secondary amino group. The compounds reduce the inner pressure of eye and exhibit selective beta-two-adrenergic antagonist effect.
The chemical structure of the novel aminopropanol derivatives of formula I is basically different from that of the prior art compounds. The activity of the novel compounds of the invention is surprising and non-predictable as though few of the novel aminopropanol derivatives of formula I exhibit antiarrhythmic activity, this activity is not based on beta-adrenergic blocking effect.
The novel aminopropanol derivatives of formula I can be prepared in several manners.
They can be prepared e.g. by reacting a cycloalkane derivative of formula II ##STR8## wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove and A represents oxygen or sulfur atom, with a substituted alkane of formula III, ##STR9## wherein L represents a group of formula H.sub.2 N--O--, or the acid-addition salt thereof, R.sup.7 is hydroxyl and R.sup.8 is a group of formula V, ##STR10## wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 stands for a chemical bond.
According to an other embodiment of the process, the novel aminopropanol derivatives of formula I can be prepared by reacting a cycloalkane derivative of formula II, wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove and A represents a group of formula .dbd.N--OH, with a halogen derivative of formula III, wherein L is halogen atom and R.sup.7 and R.sup.8 together represent an oxygen atom, and reacting a compound of formula VIII, ##STR11## thus obtained, wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove, with an amine of formula V, wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 represents hydrogen atom.
According to an other preferred embodiment of the invention, the novel aminopropanol derivatives of formula I can be prepared by reacting a compound of formula II, wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove and A represents oxygen or sulfur atom, with a glycol derivative of formula III, wherein L represents H.sub.2 N--O-- or the acid-addition salt thereof and R.sup.7 and R.sup.8 are independently hydroxyl groups, and reacting the glycol derivative of formula VI ##STR12## thus obtained, wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove, first with thionyl chloride, then with an amine of formula V, wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 represents hydrogen atom.
Those novel aminopropanol derivatives of formula I, wherein R.sup.6 represents hydrogen atom, while R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n are the same as defined hereinabove, can be reacted with a reactive benzoic acid derivative, preferably with benzoic acid anhydride, to obtain novel aminopropanol derivatives of formula I, wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n are the same as defined hereinabove and R.sup.6 is benzoyl group.
Those compounds of formula II, wherein A stands for oxygen or sulfur atom, can be prepared according to J. Chem. Soc. 1955, 1126 or J. Am. Chem. Soc. 77, 624 (1955), while those, wherein A represents a group of formula .dbd.N--OH, can be produced e.g. according to Org. Synth. Coll. Vol. II. 70.
The compounds of formula III, wherein L is H.sub.2 N--O--, R.sup.7 is hydroxyl and R.sup.8 is a group of formula V, wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 is a chemical bond, can be prepared according to J. Pharm. Sci. 58, 138 (1969).
The reaction of compounds of formula II with compounds of formula III--wherein R, R.sup.1, R.sup.2, R.sup.3, A and n are the same as defined hereinabove, L is H.sub.2 N--O-- or the acid-addition salt thereof, R.sup.7 is hydroxyl group and R.sup.8 is a group of formula V, wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 stands for a chemical bond--can preferably be carried out in an inert solvent or in a mixture of inert solvents. Such solvents may be e.g. alcohols, preferably ethanol or pyridine, triethyl amine, etc.
The temperature of the reaction can vary within wide ranges. The reaction can be completed even at room temperature, but according to our experiments the optimal reaction rate can be achieved at the boiling point of the reaction mixture.
If the novel aminopropanol derivatives of formula I are prepared by reacting a compound of formula II with a compound of formula III, wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove, L is halogen atom, A is a group of formula .dbd.N--OH, while R.sup.7 and R.sup.8 together represent an oxygen atom, and the epoxy compound of formula VIII thus obtained is aminated with a compound of formula V, wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 is hydrogen atom, then the reaction is carried out in an inert or relatively inert solvent in the presence of a basic condensing agent. As inert solvent preferably sodium amide or sodium hydride is used. Certainly the same result can be achieved when an other alkali metal amide or hydride is used as solvent. However, if an alkali metal is used as condensing agent, the alcohols, e.g. ethyl alcohol and propyl alcohols, are the most preferred solvents. If an alkali metal hydroxide is used as condensing agent, also water is a suitable solvent. (In this latter case water is a "relatively inert solvent" as it reacts with the epoxy ring after a longer reaction time and at higher temperatures.) The amination of the epoxy compound can be carried out in an inert medium, such as alcohols, e.g. ethanol, acetonitrile, dioxane, tetrahydrofurane, etc., but if the reaction is carried out by using amines of higher boiling point, it can be completed without solvent, too, as the amine serves also as a solvent.
If the novel aminopropanol derivatives of formula I are prepared by reacting a compound of formula II with a compound of formula III, wherein R, R.sup.1, R.sup.2, R.sup.3 and n are the same as defined hereinabove, L is H.sub.2 N--O-- and R.sup.7 and R.sup.8 independently represent a hydroxyl group each, the reaction can be carried out in inert solvents, e.g. in alcohols, such as methyl or ethyl alcohol, benzene and the homologues thereof, ethers, etc. in the presence of an organic base, e.g. pyridine, lutidine, triethyl amine. The reaction can also be carried out by using the excess of the organic base as solvent. The glycol derivatives thus obtained can be reacted with thionyl chloride in an inert solvent, preferably in halogenated paraffins (such as dichloroethane, dichloromethane, chloroform, etc.), and the 1,2,3-dioxathiolane-2-oxide derivative thus obtained can be reacted with an amine of formula V, wherein R.sup.4 and R.sup.5 are the same as defined hereinabove and R.sup.9 is hydrogen atom, in an inert solvent or without solvent.
Those novel aminopropanol derivatives of formula I, wherein R.sup.6 represents hydrogen atom, while R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n are the same as defined hereinabove, can be transformed into other compounds of formula I. They can be reacted with benzoic acid anhydride in an inert solvent to obtain derivatives of formula I, wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 and n are the same as defined hereinabove and R.sup.6 is a benzoyl group.
The novel aminopropanol derivatives of formula I can be transformed into pharmaceutically acceptable acid-addition salts or quaternary ammonium derivatives. For the preparation of the acid-addition salts hydrogen halides, sulfuric acid, phosphoric acid, tartaric acid, succinic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, propionic acid, etc. can be used. For the preparation of quaternary ammonium compounds the compounds of formula I are reacted with reactants suitable for quaternarization, e.g. with alkyl halides.
The novel aminopropanol derivatives of formula I may comprise one or two asymmetric carbon atoms depending on the character of the substitutents, thus one or more racemic or two or more optically active forms of compounds of formula I can be prepared. The invention covers all of the racemic and optically active forms of compounds of formula I. If the former compounds or intermediates are prepared in the form of a diastereomeric mixture, then they can be separated into the racemic or optically active isomers in a manner known per se, by e.g. fractionated distillation, crystallization, chromatography or by forming diasteromeric salts with the aid of optically active acids, such as tartaric acid, dibenzoyl tartaric acid or camphorsulfonic acid.
According to our experiments the novel aminopropanol derivatives of formula I proved to be biologically active upon testing for pharmaceutical activity. Among the observed biological activities the most significant ones are the antianginal and/or antiarrhythmic activity, inhibition of stomach secretion (gastric acid secretion), local anaesthetic, tranquillo-sedative, antiinflammatory, analgesic and in some cases calcium antagonistic activity.
The test for acute toxicity was carried out by using 10 white mice (CFLP strain) (both male and female), weighing 18 to 22 g in each dose group. The compounds of the invention were administered orally in a dose of 20 ml/kg.
After the administration of the compounds the animals were observed for 14 days. The animals were kept in a plastic box on wood chips in a room of room temperature. They could consume tap water and standard mouse feed ad libitum. The toxicity data were determined by the method of Litchfield and Wilcoxon (Litchfield, J. T., Wilcoxon, F. W.: J. Pharmacol. Exp. Ther. 96, 99/1949/).
______________________________________ Compound according to working example No. LD.sub.50 mg/kg po. ______________________________________ 4 1800 1 400 28 1500 14 900 27 about 1000 29 1300 32 more than 2000 31 about 1000 30 1100 22 900 23 130 18 more than 1000 26 more than 1000 35 600 25 900 20 more than 1000 36 700 42 more than 1000 37 more than 1000 33 more than 1000 43 800 19 800 34 more than 1000 21 700 2 600 10 900 8 800 9 700 15 more than 1000 7 more than 1000 38 more than 1000 16 more than 1000 17 more than 1000 6 more than 1000 11 more than 1000 3 more than 1000 5 more than 1000 39 more than 1000 24 more than 1000 44 600 46 more than 1000 13 more than 1000 12 1000 47 700 45 more than 1000 41 more than 1000 40 800 69 more than 1000 49 more than 1000 48 more than 1000 50 1000 52 more than 1000 51 100 to 500 53 more than 1000 54 600 55 more than 1000 ______________________________________
The narcosis potentiating effect of the compounds of the invention were examined on white mice, with 6 animals in each group. The mice were administered orally with the compounds of the invention, then both the control and the test groups were intravenously added 40 mg/kg of hexobarbital in order to make the mice sleep (Kaergard et al.).
Those animals were considered as showing positive reaction whose sleeping time was 2.5 times higher than the average sleeping time of the control group (Kaergard Nielsen, G., Magnussen, M. P., Kampmann, E., Frey, H. H.: Archt. Int. Pharmacodyn. 2, 170 (1967), and the ED.sub.50 data were calculated by using the transformed data thus obtained.
______________________________________ Compound of working example No. ED.sub.50 mg/kg po. TI ______________________________________ 28 75 20 14 80 11 27 35 29 29 30 43 32 50 &gt;40 23 16 8 18 25 &gt;40 26 140 &gt;7 35 11.5 52 20 21.5 &gt;46.5 36 14 50 42 14.5 &gt;69 37 50 &gt;20 43 50 16 19 26 31 34 145 &gt;7 9 30 23 7 70 14 38 61 16 Chlordiazepoxide 10 62 Meprobamate 260 4.2 ______________________________________